Journal
SCIENCE TRANSLATIONAL MEDICINE
Volume 10, Issue 451, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.aat3504
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Funding
- Victorian Cancer Agency [TS10-01]
- Cancer Council NSW [RG15-20]
- St. Vincent's Clinic Foundation
- Hudson Institute of Medical Research
- Paranta Biosciences Limited
- National Health and Medical Research Council of Australia [GNT100120, GNT546107]
- Petre Foundation
- Victorian Government' Operational Infrastructure Support Program
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Resistance to platinum chemotherapy is a long-standing problem in the management of lung adenocarcinoma. Using a whole-genome synthetic lethal RNA interference screen, we identified activin signaling as a critical mediator of innate platinum resistance. The transforming growth factor-beta (TGF beta) superfamily ligands activin A and growth differentiation factor 11 (GDF11) mediated resistance via their cognate receptors through TGF-beta-activated kinase 1 (TAK1), rather than through the SMAD family of transcription factors. Inhibition of activin receptor signaling or blockade of activin A and GDF11 by the endogenous protein follistatin overcame this resistance. Consistent with the role of activin signaling in acute renal injury, both therapeutic interventions attenuated acute cisplatin-induced nephrotoxicity, its major dose-limiting side effect. This cancer-specific enhancement of platinum-induced cell death has the potential to dramatically improve the safety and efficacy of chemotherapy in lung cancer patients.
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